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FRIDAY October 18, 2013—Danoprevir is an experimental drug that is being studied as a treatment for hepatitis C infection. Results of a phase 2 clinical trial are in — and they are promising.

Danoprevir is a protease inhibitor — a substance that keeps viruses from replicating. In a study published this month in the journal Gastroenterology, researchers report that it acted quickly to eliminate hepatitis C virus from the blood of 68 percent to 85 percent of the patients tested.

Treatment with danoprevir did not result in some of the side effects that often come with other protease inhibitor antiviral medications targeting hepatitis C. “Despite recent advances, the current hepatitis C treatment regimen is burdensome on the patient and prone to adverse events,” stated lead study author Patrick Marcellin, who is from the Service d’Hepatologie and Inserm CRB3, Hopital Beaujon, APHP University of Paris.

About 3.2 million people in the United States have hepatitis C, and the U.S. Centers for Disease Control and Prevention (CDC) estimate that 2 million people born between the years of 1945 and 1965 have hepatitis C, but don’t know it because they haven’t been tested.

The new international clinical trial included 237 patients with chronic hepatitis C and an average age between 47 and 50, who previously had no treatment for their infection. Half of the participants received danoprevir for 12 weeks along with interferon and ribavirin medications, which are standard treatments for hepatitis C. The levels of hepatitis C virus in their blood were compared with those of participants who took only interferon and ribavirin for the first 12 weeks of the study. Follow-up treatment included interferon and ribavirin for 24 to 48 weeks by all patients.

Hepatitis C Response to Danoprevir

Comparisons of hepatitis C levels in patients’ blood samples showed that even during the first week, taking danoprevir caused virus levels to drop precipitously. By the second week of treatment, more than half of the patients who were taking danoprevir had undetectable levels of hepatitis C virus.

Ponni V. Perumalswami, MD, Assistant Professor of Medicine at Mount Sinai School of Medicine in New York City, explained the importance of an early response to therapy. “Earlier HCV response to antiviral therapy has been shown to be associated with increased sustained virological response — that is, a cure — for HCV," she said.

“Earlier viral suppression on HCV treatment can be used to guide providers and patients on treatment,” Dr. Perumalswami added.

Study investigators found the lowest levels of virus at four to six weeks into treatment for most patients in the study. This response was sustained for more than 24 weeks. In contrast, for the group of patients who were taking only interferon and ribavirin, the lowest levels of virus were not achieved until 20 weeks.

Sustained virologic response rates were high, at 68 to 85 percent of the patients treated with danoprevir.

Hepatitis C Resistance to Danoprevir

Whether hepatitis C virus is eliminated by an antiviral therapy depends on characteristics of the virus, called the genotype. For this study, investigators included patients with hepatitis C genotype 1, but not those with other genotypes.

While most patients responded to the new antiviral drug, 1.4 percent of the patients had a virus that was already resistant to the drug. And 4 percent of patients developed resistance during the 12 weeks of treatment. Another 1 percent had resistance over the 36 weeks of follow-up. These are lower levels of resistance compared to those for the other currently available hepatitis C drugs.

Side Effects of Hep C Treatments in Perspective

“Most of the side effects from currently available treatment regimens are related to pegylated interferon and ribavirin,” said Perumalswami. This includes, but is not limited to, anemia, leukopenia (a low white blood cell count), bone marrow suppression, fatigue, fevers, chills, and rash. Newer hepatitis C drugs aim to minimize the side effects that patients experience. “A number of treatment regimens are currently under investigation and are being developed without pegylated interferon which would help alleviate many of the side effects associated with current treatments,” Perumalswami said.

Patients taking danoprevir with interferon and ribavirin in the new study had many of the same side effects that patients who took interferon and ribavirin alone experienced. Common among them were fatique, headache, nausea, insomnia, muscle aches and chills.

However, the danoprevir group did not experience the rash or frequent anemia that often come with other antiviral treatments. “The promising results from this study offer hope that danoprevir can improve the quality of life for patients suffering from this disease,” said investigator Marcellin.

The results at different doses of the new medication showed that at the highest dose of danoprevir, side effects of nausea, diarrhea and vomiting increased. In addition, some patients had higher levels of a liver enzyme that's an indicator of liver damage. This effect was reversible when the drug was stopped. Investigators discontinued use of the highest dose because of these side effects.

Next Steps in Drug Development

Because of the effectiveness of danoprevir in this clinical trial, investigators are planning further tests. The new studies will include a broader group of patients with hepatitis C, patients who had tried other medications previously, and patients who have cirrhosis of the liver. The next studies will use lower doses of the drug to ensure that patients' exposure only to the amount needed to eliminate the virus and avoid side effects.

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